The proposed project is part of a long range research effort aimed at the development of new chemotherapeutic agents and approaches. The main objective of this research is to provide new strategies for the improvement of the therapeutic effectiveness of anti-HIV agents. Rationally designed prodrug approaches are proposed to achieve effective drug penetration into the central nervous system, prolonged duration of action and decreased cell-to-cell variability of antiviral activity. In order to increase selectivity resulting in decreased cellular and systemic toxicity, the exploitation of the lack of fidelity of HIV reverse transcriptase, as a novel approach, is proposed. The project focuses on the design, synthesis and study of 1) water soluble lipophilic, membrane permeable prodrug derivatives of nucleoside and nucleotide analogs, based on the results of the initial phase of the project; and 2 novel nucleoside and nucleotide analogs capable of misincorporation into DNA by reverse transcriptase as potential inhibitors of HIV replication with enhanced selectivity. The specific aims of the project include: design, synthesis and characterization of water soluble lipophilic prodrug forms of purine and pyrimidine 2', 3'-dideoxynucleoside and nucleotide derivatives as potential anti-HIV agents; design, synthesis and study of novel nucleoside analogs capable of misincorporation into viral DNA by HIV reverse transcriptase; study of the cellular metabolism of representative analogs; determination of substrate and inhibitory activity of the 5'- triphosphate derivatives in the reaction catalyzed by HIV reverse transcriptase with chain-terminating potential, in comparison with the cellular DNA polymerases; study of mismatch error production using in vitro fidelity assays; conformational analysis of nucleoside analogs and their potential base-pairs using X-ray crystallography, molecular modeling and computer graphics techniques; evaluation of anti-HIV activity and cytotoxicity in appropriate test systems; the correlation of molecular structures, physicochemical properties and chemical reactivities with biological activities. The resulting structure- activity relationships will form the basis for shaping future research directions. With respect to the significance of the proposed research project, it is likely that in addition to their therapeutic potential, the target compounds may serve as useful tools in the study of biochemical processes in retrovirus infected cells in general and in HIV infected cells in particular.